Lewis acid-mediated selective chlorinations of silyl enolate

Article abstract of DOI:10.1021/ja0454485

A new method involving efficient, widely applicable, and highly selective α-chlorination of simple silyl enolate with Lewis acid and an α,α-dichloro-1,3-dicarbonyl controller unit was reported. Diastereoselectivity and enantioselectivity of the reaction were investigated. High reactivity and selectivity were achieved by using α,α-dichlorinated malonic ester. Copyright

Full text of DOI:10.1021/ja0454485

Published on Web 10/28/2004
Lewis Acid-Mediated Selective Chlorinations of Silyl Enolate
Yanhua Zhang, Kazutaka Shibatomi, and Hisashi Yamamoto*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received July 28, 2004; E-mail: yamamoto@uchicago.edu
Scheme 1
The selective halogenation of carbonyl compounds is a highly
useful synthetic operation for multistep synthesis since the resulting
R-halo carbonyl compounds may serve as precursors of various
derivatives.1 Although many research groups have made important
contributions to the steady improvement of this methodology, their
diastereo- and/or enantioselective versions have rarely been inves-
tigated.2,3 Obviously, a general and more efficient methodology is
required. The electrophilic halogenation of simple silyl enolate is
one of the simplest solutions by which to achieve the above goal.4
Described herein (Scheme 1) is a new method involving the
efficient, widely applicable, and highly selective R-chlorination of
simple silyl enolate with Lewis acid and an R,R-dichloro-1,3-
dicarbonyl controller unit.
Scheme 2
Table 1. Diastereoselective Chlorinations with ZrCl4 and
R,R-Dichlorinated 1,3-Dicarbonyl Compounds
As a chlorinating reagent for silyl enolates, R,R-dichloro-1,3-
dicarbonyl compound (1) was synthesized from the corresponding
1,3-dicarbonyl compound by the reaction shown in Scheme 2.5
Although R,R-dichlorinated 1,3-dicarbonyl compounds are very
weak chlorinating reagents,6 we considered that the use of a suitable
Lewis acid would substantially increase the electrophilicity of the
chlorine atoms on 1 to react with the weak nucleophilic substrates
under mild conditions. Thus, the diastereoselective chlorination of
silyl enolate was first examined with 1 in the presence of various
Lewis acids, and we were pleased to find that ZrCl4 uniquely
revealed high reactivity and selectivity7 (Table 1, left eq). The
chlorination did not proceed at all in the absence of a Lewis acid
at 0 °C to room temperature, but in the presence of ZrCl4, the
reaction proceeded smoothly, even at -78 °C.8 Moreover, dia-
stereoselectivity of the reaction was significantly influenced by the
size of the X group of 1 and the Si group of enolate (Table 1).
Finally, treatment of the silyl enolate of 4-tert-butylcyclohexanone
9
with 1 equiv of ZrCl4 and 1 in dichloromethane at -78 °C
quantitatively gave 2-chloro-4-tert-butylcyclohexanone, with a ratio
up to 19:1 (trans:cis). The selectivity of this method, as well as the
reactivity, is much higher than that of the reported reaction10 (Table
1, right eq). In most cases, R-monochlorinated 1,3-dicarbonyl
compound was recovered in >90% yields and can be re-used after
chlorination by the reaction shown in Scheme 2.
a Determined by GC analysis. Yields of the reaction are >90%.
effects of silyl groups). Although the reaction of trimethylsilyl
enolate 6a with 1c afforded only 31% ee of 13 (entry 13), the use
of tert-butyldimethylsilyl enolate afforded 13 with 87% ee (entry
14). The reaction of silyl enolate, having a five- or seven-membered
ring, also afforded the corresponding R-chloroketones in high
enantioselectivity (entries 8-12, up to 98% ee). Up to 90% ee was
obtained for acyclic substrates (entries 17 and 18). One unique
advantage of this reaction is that we can obtain R-chlorinated
product with opposite configuration by simply changing the R group
on 1 to its opposite isomer.
The exact reaction mechanism is not yet clear. However, we
assume that the high asymmetric induction observed came from
the high reactivity of the Lewis acid (ZrCl4) as well as the unique
structural feature of chiral malonic ester. After the coordination of
zirconium with two carbonyl oxygens, a C2 symmetrical six-
membered ring is apparently generated, and the carbon-chlorine
Encouraged by these results, we prepared several optically active
chlorinating reagents (1a-d), most of which have aromatic
substituents at the 2-position of cyclohexanol, to perform asym-
metric chlorination of silyl enolate. The structural optimization of
chiral malonic esters and the scope of substrates are summarized
in Table 2.11 The yields of all R-chloroketones were >90%; as
expected, the larger the sterical substituents at the 2-position of
cyclohexanol, the higher the enantioselectivity they gave (entry 1,
42% ee with 1a; entry 2, 67% ee with 1b; entry 3, 80% ee with
1c). However, the most bulky chlorinating reagent, 1d, was not
the best choice, except for substrate 4 (entries 8-10, up to 98%
ee). In most cases, 1c gave a corresponding product with the highest
enantioselectivity. It was also noteworthy that the steric hindrance
of the silyl group had a significant influence on the asymmetric
induction (entries 3, 4, 6, and 13-16) (Table 1 also indicated the
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10.1021/ja0454485 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Chlorinations of Silyl Enolate with ZrCl4 and
Chiral R,R-Dichlorinated Malonic Estera
Scheme 3. Proposed Transition State
paradigm for enantioselective chlorination of carbonyl compounds,
which could further expand the use of Lewis acids in organic
synthesis. Obviously, the next steps include rendering the suitable
ligand systems amenable to multiturnover and asymmetric catalysis.
Acknowledgment. This work was supported by the Japan
Science and Technology Agency (JST) and the University of
Chicago.
Supporting Information Available: Experimental procedures and
characterization of compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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a Reactions were carried out at -78 °C in dichloromethane in the
presence of 1 equiv of ZrCl4 and chiral R,R-dichlorinated malonic ester.
Yields of the reaction are >90%. b Determined by HPLC analysis, except
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GC analysis.
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Development of using catalytic amounts of Lewis acid is under investiga-
tion.
bonding was weakened. Those two chlorine atoms are equivalent,
either one can be released as a cation, which reacted with silyl
enolate in the cage formed by two chiral functional groups and
gave the expected R-chlorinated product. When all of these results
are taken into account, the transition state assembly shown in
Scheme 3 is most likely.
In summary, we have described a new concept of enantioselective
R-chlorination of ketones through chlorination of corresponding
silyl enolates using R,R-dichlorinated malonic ester as a chlorine
source and chirality controller in the presence of a Lewis acid. We
believe that the idea expressed herein provides a useful new
(10) Brummond, K. M.; Gesenberg, K. D. Tetrahedron Lett. 1999, 40, 2231-
2234.
(11) To the solution of optically active R,R-dichlorinated malonate ester (0.5
mmol) in CH2Cl2 (2.0 mL), cooled to -78 °C, was added ZrCl4, followed
by the solution of silyl enolate (0.5 mmol) in CH2Cl2 (2.0 mL) under a
nitrogen atmosphere. The reaction was stirred at -78 °C until all of the
starting material was consumed and was then quenched by a saturated
NaHCO3 aqueous solution. Extraction with CH2Cl2, followed by flash
column chromatography on silica gel, gave pure R-chlorinated product.
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